Anti-angiogenic and anti-metastatic activity of synthetic phosphoethanolamine.

Abstract

BACKGROUND:

Renal cell carcinoma (RCC) is the most common type of kidney cancer, and represents the third most common urological malignancy. Despite the advent of targeted therapies for RCC and the improvement of the lifespan of patients, its cost-effectiveness restricted the therapeutic efficacy. In a recent report, we showed that synthetic phosphoethanolamine (Pho-s) has a broad antitumor activity on a variety of tumor cells and showed potent inhibitor effects on tumor progress in vivo.

METHODOLOGY/PRINCIPAL FINDINGS:

We show that murine renal carcinoma (Renca) is more sensitive to Pho-s when compared to normal immortalized rat proximal tubule cells (IRPTC) and human umbilical vein endothelial cells (HUVEC). In vitro anti-angiogenic activity assays show that Pho-s inhibits endothelial cell proliferation, migration and tube formation. In addition, Pho-s has anti-proliferative effects on HUVEC by inducing a cell cycle arrest at the G2/M phase. It causes a decrease in cyclin D1 mRNA, VEGFR1 gene transcription and VEGFR1 receptor expression. Pho-s also induces nuclear fragmentation and affects the organization of the cytoskeleton through the disruption of actin filaments. Additionally, Pho-s induces apoptosis through the mitochondrial pathway. The putative therapeutic potential of Pho-s was validated in a renal carcinoma model, on which our remarkable in vivo results show that Pho-s potentially inhibits lung metastasis in nude mice, with a superior efficacy when compared to Sunitinib.

CONCLUSIONS/SIGNIFICANCE:

Taken together, our findings provide evidence that Pho-s is a compound that potently inhibits lung metastasis, suggesting that it is a promising novel candidate drug for future developments.

• Authors: Adilson Kleber Ferreira, Vanessa Morais Freitas, Débora Levy, Jorge Luiz Mária Ruiz, Sergio Paulo Bydlowski, Rose Eli Grassi Rici, Otaviano Mendonça R Filho, Gilberto Orivaldo Chierice, Durvanei Augusto Maria
• Journal: PloS one (PLoS One) Vol. 8 Issue 3 Pg. e57937 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 23516420 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inhibitors
• Antineoplastic Agents
• Ethanolamines
• Indoles
• Pyrroles
• Cyclin D1
• phosphorylethanolamine
• Vascular Endothelial Growth Factor Receptor-1
• Caspase 3
• Sunitinib

Topics

• Angiogenesis Inhibitors (chemical synthesis, pharmacology, toxicity)
• Animals
• Antineoplastic Agents (chemical synthesis, pharmacology, toxicity)
• Apoptosis (drug effects)
• Carcinoma, Renal Cell (drug therapy, pathology)
• Caspase 3 (metabolism)
• Cell Cycle Checkpoints (drug effects)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Cyclin D1 (genetics)
• Cytoskeleton (drug effects)
• Ethanolamines (chemical synthesis, pharmacology, toxicity)
• Gene Expression Regulation, Neoplastic (drug effects)
• Human Umbilical Vein Endothelial Cells (drug effects)
• Humans
• Indoles (pharmacology, toxicity)
• Kidney Tubules, Proximal (drug effects)
• Lung Neoplasms (drug therapy, secondary)
• Male
• Mice
• Mice, Inbred BALB C
• Mitochondria (drug effects, metabolism)
• Neoplasm Metastasis (drug therapy)
• Neovascularization, Pathologic (drug therapy)
• Oxidation-Reduction (drug effects)
• Pyrroles (pharmacology, toxicity)
• Rats
• Sunitinib
• Transcription, Genetic
• Vascular Endothelial Growth Factor Receptor-1 (genetics)
• Wound Healing (drug effects)